Hyper-inflammation and skin destruction mediated by rosiglitazone activation of macrophages in IL-6 deficiency

Lopa M. Das, Julie Rosenjack, Liemin Au, Pia S. Galle, Morten B. Hansen, Martha K. Cathcart, Thomas S. McCormick, Kevin D. Cooper, Roy L. Silverstein, Kurt Q. Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Injury initiates recruitment of macrophages to support tissue repair; however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the peroxisome proliferation-activated receptor-γ agonist, rosiglitazone (Rosi), a medication recently reintroduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates proinflammatory macrophages. This is observed in both IL-6-deficient mice and control wild-type mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6 deficiency in human diseases. IL-6 deficiency when combined with Rosi-mediated upregulation of suppressor of cytokine signaling 3 leads to an altered ratio of nuclear signal transducer and activator of transcription 3/NF-κB that allows hyper-induction of inducible nitric oxide synthase (iNOS). Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6 deficiency.

Original languageEnglish (US)
Pages (from-to)389-399
Number of pages11
JournalJournal of Investigative Dermatology
Issue number2
StatePublished - Feb 13 2015

ASJC Scopus subject areas

  • Dermatology
  • Molecular Biology
  • Biochemistry
  • Cell Biology


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